ABSTRACT
Modern lifestyles have altered diet and metabolic homeostasis, with increased sugar intake, glycemic index, and prediabetes. A strong positive correlation between sugar consumption and diabetic incidence is revealed, but the underlying mechanisms remain obscure. Here we show that oral intake of long-term oscillating glucose (LOsG) (4 times/day) for 38 days, which produces physiological glycemic variability in rats, can lead to ß-cells gaining metabolic memory in reactive oxygen species (ROS) stress. This stress leads to suppression of forkhead box O1 (FoxO1) signaling and subsequent upregulation of thioredoxin interacting protein, inhibition of insulin and SOD-2 expression, re-expression of Neurog3, and ß-cell dedifferentiation and functional failure. LOsG-treated animals develop prediabetes exhibiting hypoinsulinemia and glucose intolerance. Dynamic and timely administration of antioxidant glutathione prevents LOsG/ROS-induced ß-cell failure and prediabetes. We propose that ROS stress is the initial step in LOsG-inducing prediabetes. Manipulating glutathione-related pathways may offer novel options for preventing the occurrence and development of diabetes.
Subject(s)
Blood Glucose/drug effects , Cell Dedifferentiation/drug effects , Glucose/toxicity , Glutathione/pharmacology , Insulin-Secreting Cells/drug effects , Animals , Antioxidants/metabolism , Apoptosis/drug effects , Blood Glucose/metabolism , Cell Cycle Proteins/genetics , Cell Cycle Proteins/metabolism , Cell Dedifferentiation/genetics , Female , Glucose/metabolism , Glucose Intolerance/metabolism , Insulin/metabolism , Insulin-Secreting Cells/cytology , Insulin-Secreting Cells/metabolism , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Pancreas/drug effects , Pancreas/metabolism , Prediabetic State/metabolism , Rats , Rats, Sprague-Dawley , Reactive Oxygen Species/metabolism , Superoxide Dismutase/genetics , Superoxide Dismutase/metabolismABSTRACT
BACKGROUND: The neutrophil-lymphocyte ratio (NLR) has been considered as an inflammatory marker in various disorders, but it is not clear whether the NLR is also elevated with hidden diabetes (HD), which is normal in fasting blood glucose (FBG) but abnormal in the oral glucose tolerance test (OGTT). MATERIALS AND METHODS: An HD animal model for 27 days and an animal model with oscillating glucose (OG) for 7 days were applied on adult female Sprague-Dawley rats. OGTT, leukogram analysis, histology, and immunohistochemistry were carried out. RESULTS: In HD rats, the percentage of neutrophils increased but the percentage of lymphocytes decreased; hence, the NLR rose relative to sham. This may be a result of the OG levels often experienced by diabetic subjects, as normal rats given OG (6 g/kg/6 h) for 7 days had significantly reduced lymphocyte numbers and increased NLR compared with the values before and 1 h after oral glucose administration during OGTT. Glucose-induced disarrangement of partitions of circulating immune cells and NLR was involved in the increase in oxidative stress, as these changes were totally blocked by the antioxidant glutathione (GSH). GSH (50 mg/kg/6 h) totally blocked the glucose-induced alterations in lymphocyte and NLR values. CONCLUSION: HD associated with elevation of NLR values may be partly attributed to a homeostasis disorder of the innate inflammatory state, caused by oscillating hyperglycemia. Acute high glucose administration produced a significant decrease in lymphocyte number. OG administration potentiated this effect and increased the NLR value, which was blocked by GSH, suggesting that reactive oxygen species play a critical role in maintaining lymphocyte numbers.
